A sustained release dosage form may be defined as a preparation which releases a drug, in vivo, at a considerably slower rate than is the case from an equivalent dose of a conventional (non-sustained release) dosage form. The objective of employing a sustained release product is to obtain a satisfactory drug response while at the same time, reducing the frequency of administration. An example of a drug which is popularly used in a sustained release form is chlorpheniramine maleate. In conventional form, the drug may be given as 4 mg doses every four (4) hours or in sustained release form as 12 mg every twelve (12) hours.
Sustained release compositions for the sequential or timed release of medicaments are well known in the art. Generally, such compositions contain medicament particles, normally administered in divided doses two (2) or three (3) times daily, mixed with or covered by a coating material which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the medicament may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the nature and thickness of the coating material.
It is known that different pharmaceutical preparations of the same active ingredient will result in different bioavailabilities of the active ingredient to the mammal. Bioavailability or biological availability may be defined as the percentage of the drug liberated from the dosage form administered that becomes available in the body for biological effect. Different formulations of the same drug can vary in bioavailability to a clinically relevant extent and variation may even occur between batches of the same product due to subtle variations in manufacturing procedures.
Many drugs that are usually administered in tablet or capsule form have a low solubility in biological fluids. For many drugs of low solubility, there is considerable evidence that the dissolution rate, partially or completely controls the rate of absorption. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the granulation process, compression forces (in tablet manufacturing), surface area available for dissolution and environmental factors such as agitation in the stomach and the presence of food. Due to these numerous factors, specific formulations play an important role in the preparation of prolonged action solid dosage forms.
Epilepsy is an ancient disease which affects about 1% of the global population. Despite the progress made in antiepileptic drug therapy, there are still many patients who continue to suffer from uncontrolled seizures and medication toxicity. At present, only four (4) major antiepileptic drugs are in use: phenobarbital, phenytoin sodium, carbamazepine and valporic acid.
Pharmacological activity, in general, and antiepileptic activity in particular, correlate better with a concentration of the drug in the blood (or in some other biophase) than with the administered dose. This phenomenon is due, in part, to variability in drug absorption and disposition between and within individuals, particularly when the drug is given orally. Optimizing drug therapy aims at achieving and maintaining therapeutic and safe drug concentrations in the patient's plasma. It would thus be advantageous that the patient receive a once- or twice-daily dosage regimen.
Phenytoin is 5,5-diphenyl-2,4-imidazolidinedione. It is a well-known pharmaceutical agent having anti-convulsant and antiepileptic activity. Due to phenytoin's poor solubility in water, phenytoin sodium, of empirical formula C.sub.15 H.sub.11 N.sub.2 NaO.sub.2, which is much more soluble, is employed in the preparation of injectable solutions of the drug and in solid enteral dosage forms.
While phenytoin is the antiepileptic drug of choice for most types of epileptic seizures, except for petit mal, therapeutic drug monitoring is required because of the difficulty in maintaining an effective therapeutic plasma level of between 10 and 20 .mu.g/ml. In addition to the problems of narrow therapeutic plasma levels, phenytoin has exhibited great variations in bioavailability following its oral administration to patients because of its poor water solubility.
With even the new approaches to phenytoin delivery (i.e., Parke-Davis' Dilantin.RTM. Kapseals.RTM., which are 100 mg extended phenytoin sodium capsules), it is still necessary for patients to take the drug several times a day to maintain an effective therapeutic plasma level without side effects. While many encapsulation techniques have been attempted, none have been found to be satisfactory. Karakasa et al., Biol. Pharm. Bull., 17(3) 432-436 (1994) in an article entitled "Sustained Release of Phenytoin Following the Oral Administration of Phenytoin Sodium/Ethylcellulose Microcapsules in Human Subjects and Rabbits", studied the release patterns of phenytoin as the sodium salt in combination with ethylcellulose. The phenytoin sodium microcapsules were prepared by mixing 80 weight % of the phenytoin sodium in a 10% (w/v) ethylcellulose solution in ethylacetate. The suspension was stirred and n-pentane was added dropwise until a phase separation occurred and the microcapsules were obtained. The microcapsules were collected on filter paper, dried and stored. Karakasa et al. point out that following the oral administration of phenytoin sodium, the salt might be easily transferred into free-phenytoin in the acidic fluids of the stomach. As free-phenytoin is practically insoluble in water, its absorption might be incomplete in the gastrointestinal tract. On the other hand, while passing through the stomach, the volume of water penetrating into the ethylcellulose microcapsules might be minimal. Thus, most of the phenytoin sodium in the microcapsules might not be converted into free-phenytoin. This reference fails to suggest a dosage form wherein a portion of the active ingredient is released in the stomach and the remaining portion is released in the intestines.
A review article by Boxenbaum in Drug Development & Industrial Pharmacy, 1982, 8(v), 1-25, entitled "Physiological and Phamacokinetic Factors Affecting Performance of Sustained Release Dosage Forms" actually suggests that sustained release formulations for drugs such as phenytoin are unnecessary. Boxenbaum points out that dosing schedules of once a day versus three times daily produce similar plasma curves. This results from both the slow absorption, disposition of the drug and the low solubility.
It is the inventor's position that slow release, delayed release, prolonged release or sustained release phenytoin is a desirable objective. Controlled release oral dosage forms of drugs with long half lives, such as phenytoin, have been previously disregarded for sustained release formulation since they produce little change in the blood concentration after multiple doses have been administered. The existence of such products can, however, be justified, on the basis of their ability to minimize toxicity and the occurrence of adverse reactions and as providing greater patient convenience and thus, better patient compliance.
Bialer in an article entitled, "Pharmacokinetic Evaluation of Sustained Release Formulations of Antiepileptic Drugs . . . Clinical Implications" in Clinical Pharmacokinetics 22(1): 11-21 1992, also suggests that phenytoin is not a suitable candidate for sustained release formulations. What Bialer and Boxenbaum have failed to realize is that through the novel use of the physical properties of phenytoin sodium and drugs like phenytoin sodium, one can prepare a sustained release formulation that is beneficial to the patient.
The dosage form according to this invention has an essentially unprotected layer of active ingredient that is immediately released into the gastric juices of the stomach and a second layer of active ingredient that is protected by an enteric coating. This second portion of the dose is made available subsequent to passage into the duodenum. The drug delivery system according to the present invention provides an unusually stable drug concentration profile in the plasma. Further, patients will benefit from such a formulation since many drugs. like phenytoin have narrow therapeutic windows which require multiple (3 or more) daily dosings.
Further, Irvin et al., in an article in Pharmaceutical Research, Vol. 8, No. 2, 1991, entitled "Computer-Aided Dosage Form Design. III. Feasibility Assessment for an Oral Prolonged-Release Phenytoin Product" have also emphasized that phenytoin is not an acceptable candidate for prolonged release dosage forms. They go on to note that dosage forms which traverse the stomach tend to be expelled before the release of the phenytoin is complete. These teachings again fail to realize that a novel dosage form, having protected and unprotected components, can be effectively used to prepare a sustained release formula for drugs with pH dependent solubilities.
Deasy, Critical Reviews in Therapeutic Drug Carrer Systems, 8(1): 39-89 (1991) in an article entitled "Microencapsulation of Drugs by Pan and Air Suspension Techniques" states that drugs such as phenytoin with half-lives greater than six (6) hours, tend to have inherent sustained release properties and benefit little from prolonged released preparations. The Deasy article goes on to comment that drugs such as phenytoin, with narrow ranges of therapeutic plasma levels, present special problems when being formulated as sustained release preparations. This reference also provides a good general discussion of microencapsulation dosage forms prepared by the pan and air suspension methodologies.
A paper by Bourgeois entitled "Important Pharmnacokinetic Properties of Antiepileptic Drugs" in Epilepsia, Vol. 36 (Supp. 5) 1995, discusses the important pharmnacokinetic properties of antiepileptic drugs. The author states that a drug's rate of absorption profile is described by its absorption constant (k.sub.abs). A high absorption constant results in early and high peak serum concentrations. A high (k.sub.abs) value also results in greater fluctuations in drug levels compared with the steadier concentrations resulting from lower (k.sub.abs) values. A lower absorption constant can often be produced by formulating an otherwise rapidly absorbed drug in a slow release preparation. However, enteric coated preparations do not alter a drug's (k.sub.abs) value; they merely delay absorption. Enteric coating is designed to prevent absorption in the acidic environment of the stomach. Consider for example, a patient who has received a single dose of enteric coated valproate. For the first few hours after dosing, serum measurements will fail to detect any drug in the blood. Not until the tablet reaches the alkaline environment of the duodenum does the serum concentration rapidly increase, ultimately achieving a profile similar to that of an uncoated preparation of valproate. Therefore, the enteric coating merely shifts the time concentration profile to the right.
In a publication in Clinical Pharmacy, Vol. 3, November-December 1984, entitled "Absorption characteristics of three phenytoin sodium products after administration of oral loading doses" by Goff et al., the absorption characteristics of three (3) phenytoin sodium products after administration of oral loading doses is evaluated. Goff et al. suggest that the administration of intravenous phenytoin has been associated with serious adverse effects, including cardiac arrhythmias and hypotension. The reported study was conducted to determine the effect of different phenytoin sodium preparations on the rate and extent of absorption following the administration of oral phenytoin loading doses. Goff et al. report that the absorption following oral administration of the phenytoin sodium solution was found to be erratic and highly variable among subjects. In the acid medium of the stomach, phenytoin sodium is rapidly changed to phenytoin acid with subsequent precipitation. The authors of this reference suggest that following the administration of the phenytoin sodium solution, the solubilizing agents were rapidly absorbed from the stomach and this could have resulted in the precipitation of the poorly soluble phenytoin acid in the stomach. A similar mechanism was proposed for the poor absorption of phenytoin following intra-muscular administration.
In an article by Yazici et al., entitled "Phenytoin Sodium microcapsules: Bench Scale Formula, Process Characterization and Release Kinetics" in Pharmaceutical Development and Technology, 1(2), 175-183 (1996), the preparation of phenytoin sodium microcapsules using ethylcellulose and methyl acrylic acid copolymers (Eudragit.RTM. S-100 and L-100) as coating materials is reported. The phenytoin sodium microcapsules were formulated by an organic phase separation and granule coating method. The optimum phenytoin sodium-to-ethylcellulose ratio of 1:2.3 was reported. The authors report that phenytoin sodium is a problem material as far as drug absorption is concerned as the rate determining step of phenytoin absorption is its release from dosage forms. The optimized experimental dosage forms were evaluated against sustained-action, commercially available capsules and found to give superimposable release characteristics. The authors fail to suggest that the dose of phenytoin sodium, in microcapsular form, be divided between the enteric coating. Neither the microcapsules nor the Yazici et al. method of production are at all similar to the presently claimed dosage form wherein the core comprise 25-75% of an effective amount of a therapeutic agent over the enteric coating and finally a coating of a low pH soluble protective coating.
U.S. Pat. No. 4,968,508 to Oren et al. relates to a matrix composition for sustained drug delivery which is comprised of an active agent, a hydrophilic polymer and an enteric polymer. The enteric polymer is impermeable to gastric fluids and aids in retarding drug release in regions of low pH, thus allowing lower levels of hydrophilic polymer to be employed. Oren et al. suggest that this approach is useful in sustaining the release of numerous active agents whose solubility declines as the pH is increased, a characteristic of weekly basic drugs. The Oren et al. sustained release matrix was prepared using conventional hydrogel technology. This patent does not suggest nor disclose the division of a given dose of active agent by an enteric coating. The enteric coating only releasing the remaining portion of the active after entry into the duodenum.
U.S. Pat. No. 4,994,260 to Kallstrand et al. relates to a pharmaceutical preparation for controlled release of a pharmaceutically active substance prepared by mixing, in an aqueous carrier, a pharmaceutically active substance encapsulated in a coating and 60-99% by weight of a release controlling substance selected from the group consisting of polysaccharides, oligosaccharides, disaccharides, monosaccharides, polyhydroxyalchohols and mixtures thereof. This patent describes the use of Eudragit.RTM. E 100 and sucrose to make the dosage form. The Eudragit.RTM. E 100 is a polymer soluble in acid.
U.S. Pat. No. 5,188,836 to Muhammad et al. discloses a semi-enteric, sustained release pharmaceutical consisting of a biologically active composition layered on an inert core and an outer inert coating consisting of a water insoluble methacrylic acid polymer, a water soluble sugar alcohol, a food grade acid and a plasticizer characterized by a two-tiered solubility profile in the human digestive tract. The dosage forms of this reference initially dissolve in the stomach and thereafter completely dissolves and is absorbed in the intestine. This patent discloses the use of Eudragit.RTM. L30D as a major coating constituent. In this reference, the release characteristics of Eudragit.RTM. L30D polymer are modified so that a semi-enteric formulation is created. The dissolution characteristics of Eudragit.RTM. L30D are modified through the inclusion of a water soluble bulking agent such as a sugar alcohol.
U.S. Pat. No. 5,102,668 to Eichel et al. discloses a pharmaceutical preparation that contains multiple units of microparticles comprising a granular drug that is less soluble at low pH and more soluble at high pH. The granular drug is admixed with or surrounded by a pH controlled material which is formed from at least one polymer that is hydrophilic at low pH and hydrophobic at higher pH. The pH controlled material is in a ratio with the granular drug such that the resulting sustained release pharmaceutical preparation is independent of the pH environment. Eudragit.RTM. E 100 is disclosed as a polymer which is useful in the invention since it is pH controlled.
U.S. Pat. No. 5,229,131 to Amidon et al. discloses a drug delivery system for administering a drug in controlled pulse doses in a aqueous environment over a predetermined dosage period of time. A unitary body contains a plurality of subunits. Each of the subunits has a core portion which contains an individual dose of the drug. The core is surrounded by a respectively associated coating portion which is formed of selected first and second polymer materials. The water permeable polymers are disclosed as including cellulose acetate, Eudragit.RTM. RS and Eudragit.RTM. R30D. The drug delivery system of the '131 patent is disclosed as being useful with beta-adrenergic blockers and antiepileptic drugs such as phenytoin.
U.S. Pat. No. 5,238,686 to Eichel et al. discloses a dual walled coated medicament having a water soluble core drug, an inner wall microencapsular coating and an outer wall enteric coating. By enterically coating the microcapsules, the release of core drug into the stomach is greatly impeded and the delivery of the drug is substantially delayed until the coated microcapsules reach the intestine. The dual walled medicament of the '686 patent is claimed to release less than 10% per hour of said drug while in the stomach, but will slowly release said drug in the intestines to provide adequate levels for eight (8) or more hours without resulting in excessively high drug levels at any time.
From a review of the prior art, it is quite evident that a need still remains for a sustained release system for drugs with pH dependent solubilities, such as phenytoin sodium, which provide initial therapeutic levels of the drug, delays the delivery of another fraction of the drug to eliminate excess concentrations for about 1-5 hours and then, sustains the release of that delayed fraction to provide adequate blood plasma drug levels for 12 or more hours.